Pyridinone diketo acids: inhibitors of HIV replication

ABSTRACT

A new class of diketo acids constructed on pyridinone scaffolds, designed as inhibitors of HIV replication through inhibition of HIV integrase, is described. These compounds are useful in the prevention or treatment of infection by HIV and in the treatment of AIDS and ARC, either as the compounds, or as pharmaceutically acceptable salts, with pharmaceutically acceptable carriers, used alone or in combination with antivirals, immunomodulators, antibiotics, vaccines, and other therapeutic agents, especially other anti-HIV compounds (including other integrase-based anti-HIV agents). Methods of treating AIDS and ARC and methods of treating or preventing infection by HIV are also described.

RELATED APPLICATIONS AND GRANT SUPPORT

This application claims the benefit of priority of provisionalapplication number U.S. No. 60/831,990, filed Jul. 19, 2006, andprovisional application number U.S. No. 60/920,196, filed Mar. 27, 2007,both entitled, “Pyridinone Diketo Acids: Inhibitors of HIV Replication”,each of which applications is incorporated by reference in its entiretyherein.

The work leading to the instant patent application was supported in partby a grant from the National Institutes of Health, award number A143181.Consequently, the United States government retains certain rights in theinvention.

FIELD OF THE INVENTION

The present invention relates to the field of antiviral therapy, inparticular the treatment of HIV infections in humans, includingcombination therapy.

BACKGROUND OF THE INVENTION

The human immunodeficiency virus, HIV, encodes three key viral enzymesthrough its pol gene and these enzymes are critical for the replicationof this virus [Fauci, Science, 239, 617-622 (1988); Katz & Skalka, Annu.Rev. Biochem., 63, 133-173 (1994); Frankel, Annu. Rev. Biochem., 67,1-25 (1998)]. For this reason, these enzymes of the pol gene have beentargeted as potential sites of attack in the development of HIVantiviral chemotherapeutic agents [De Clercq, J. Med. Chem. 38,2491-2517 (1995); Clin. Microbiol. Rev., 10, 674-693 (1997); De Clercq,Nature Reviews: Drug Discovery, 11, 13-25 (2002); De Clercq, J. Med.Chem. 48, 1297-1313 (2005)]. Drug discovery involving two of theseenzymes, HIV reverse transcriptase (RT) and HIV protease (PR), andsubsequent clinical applications of some of these therapeutic agents incombination therapy for the treatment of acquired immunodeficiencysyndrome (AIDS) and AIDS related complex (ARC) in HAART (highly-activeantiretroviral therapy) have suggested that this methodology oftargeting key viral enzymes represents a useful approach in antiviralchemotherapy [Johnson & Gerber, in “Advances in Internal Medicine,” vol.44. Mosby: St. Louis, 1-40 (2000); De Clercq, Nature Reviews: DrugDiscovery, 11, 13-25 (2002); Miller & Hazuda, Current Opinion inMicrobiology, 4, 535-539 (2001); Asante-Appiah & Skalka, Adv. VirusRes., 52, 351-369 (1999); Nair, in “Recent Advances in Nucleosides:Chemistry and Chemotherapy,” Elsevier Science: Netherlands, 149-166(2002); DeClercq, Intl. J. Biochem. Cell Biol. 36, 1800-1822 (2004)].While HIV RT and HIV PR have been extensively studied with respect totherapeutics, the third enzyme of the pol gene, HIV integrase, hasreceived much less consideration [Miller & Hazuda, Current Opinion inMicrobiology, 4, 535-539 (2001); Nair, Rev. Med. Virol., 12, 179-193(2002); Nair, Current Pharmaceutical Design, 9, 2553-2565 (2003);Pommier, et al., Nature Rev. Drug Discovery 4, 236-248 (2005); Nair,Frontiers in Med. Chem. 2, 3-20 (2005)].

At present there are no drugs in clinical use for HIV/AIDS where themechanism of action is inhibition of HIV integrase. HIV-1 integrase is aprotein of 32 kDa encoded at the 3′-end of the pol gene [Asante-Appiah &Skalka, Adv. Virus Res., 52, 351-369 (1999); Esposito & Craigie, Adv.Virus Res., 52, 319-333 (1999)]. It is involved in the integration ofHIV DNA into the host cell chromosome. Because integrase has no humancounterpart and because it plays the significant role of completing theinvasion of the human cell cell by HIV, it is an attractive target forthe discovery of inhibitors of therapeutic potential.

Incorporation of HIV DNA into host chromosomal DNA in the cell nucleuscatalyzed by integrase apparently occurs by a specifically definedsequence of 3′-processing or tailoring and strand transfer/integrationreactions [Asante-Aplpiah & Skalka, Adv. Virus Res., 52, 351-369 (1999);Esposito & Craigie Adv. Virus Res., 52, 319-333 (1999)]. Prior to theinitiation of the integration process, there is assembly of viral DNA,previously produced by reverse transcription, on the integrase. HIVintegrase recognizes specific sequences in the LTRs of viral DNA.Following assembly of viral DNA on integrase, the processing of viralDNA occurs where there is site specific endonuclease activity and twonucleotides are cleaved off from each 3′-end of the double helical viralDNA to produce the tailored viral DNA recessed by two nucleotides andbearing a terminal CAOH-3′. For this initial 3′-processing step,integrase apparently activates the phosphodiester bond towards cleavage.The recessed viral DNA thus produced is joined in the next step to hostcell DNA in the nucleus through a trans-esterification reaction. In thisstep, integrase positions the 3′-OH end of the viral DNA fornucleophilic attack on the phosphodiester bond in the host DNA. In thesubsequent step, there is cleavage of 4-6 bp in host DNA and thecoupling involves the joining of processed CAOH-3′ viral DNA ends to the5′-phosphate ends of the host DNA. Finally, there is repair of theresulting gapped intermediate mediated by host cell enzymes, although arole here for the integrase is also possible.

A variety of compounds are inhibitors of HIV integrase but some of thesecompounds are non-specific inhibitors of the enzyme while evidencesuggests that others may possess some specificity. The various classesinclude nucleotides, oligonucleotides, dinucleotides, and miscellaneoussmall molecules including heterocyclic systems, natural products, diketoacids, sulfones and others [Nair, Rev. Med. Virol., 12, 179-193 (2002);Nair, Current Pharmaceutical Design, 9, 2553-2565 (2003); Chi and Nair,Bioorg. Med. Chem. Lett. 14, 4815-4817 (2004); Nair and coworkers, J.Am. Chem. Soc., 122, 5671-5677 (2000)].

The class of previously studied compounds that are most directlyrelevant to this patent are diketo acids with aryl or heteroarylsubstitutions. Some of these compounds are inhibitors of HIV integrase,but most commonly of only the strand transfer step. The integraseinhibition data have been reported in several scientific publications[Wai, et al., “4-Aryl-2,4-dioxobutanoic acid inhibitors of HIV-1integrase and viral replication in cells,” J. Med. Chem. 43, 4923-4926(2000); Pais, G. C. G., et al., “Structure activity of3-aryl-1,3-diketo-containing compounds as HIV-1 integrase inhibitors,”J. Med. Chem. 45, 3184-3194 (2002); Marchand, C., et al., “Structuraldeterminants for HIV-1 integrase inhibition by β-diketo acids,” J. Biol.Chem. 277, 12596-12603 (2002); Sechi, M., et al., “Design and synthesisof novel indole beta-diketo acid derivatives as HIV-1 integraseinhibitors,” J. Med. Chem. 47, 5298-5310 (2004); Zhang, et al.,“Azido-containing aryl β-keto acid HIV-1 integrase inhibitors,” Bioorg.Med. Chem. Lett. 13, 1215-1219 (2003), Nair, et al., “HIV integraseinhibitors with nucleobase scaffolds: discovery of a highly potentanti-HIV agent,” J. Med. Chem. 49, 445-447 (2006); Nair, et al.,“Conceptually novel HIV integrase inhibitors with nucleobase scaffolds:discovery of a highly potent anti-HIV agent,” Antiviral Res. 70, A26(2006); Sato, et al., “Novel HIV-1 integrase inhibitors derived fromquinolone antibiotics,” J. Med. Chem. 49, 1506-1508 (2006); Nair et al.,“Beta-diketo acids with purine nucleobase scaffolds: novel selectiveinhibitors of the strand transfer step of HIV integrase,” Bioorg. Med.Chem. Lett. 16, 1920-1923 (2006), Chi et al., “A novel diketo phosphonicacid that exhibits specific, strand-transfer inhibition of HIV integraseand anti-HIV activity,” Bioorg. Med. Chem. Lett. 17, 1266-1269 (2007)].Other publications in the area are of peripheral relationship to thispatent application.

The mechanism of inhibition of HIV integrase by diketo acids may be theresult of interaction of the functional groups on these compounds withmetal ions in the active site of integrase, resulting in a functionalsequestration of these critical metal cofactors [Grobler, J. A., et al.,Proc. Natl. Acad. Sci. U.S.A. 99, 6661-6666 (2002)].

Related patents to this application are: Selnick, H. G. et al., (Merck &Co. Inc.), “Preparation of nitrogen-containing4-heteroaryl-2,4-dioxobutyric acids useful as HIV integrase inhibitors,”WO 9962513; Young, S. D., et al., (Merck & Co. Inc.), “Preparation ofaromatic and heteroaromatic 4-aryl-2,4-dioxobutyric acid derivativesuseful as HIV integrase inhibitors,” WO 9962897; Fujishita, T., et al.,Yoshinaga, T., et al. (Shionogi & Co. Ltd.), “Preparation of aromaticheterocycle compounds having HIV integrase inhibiting activities,” WO0039086; Akihiko, S., (Shionogi & Co. Ltd.), “Medicinal compositionscontaining propenone derivatives,” WO 0196329; Payne, L. S., et al.,(Merck & Co. Inc.; Tularik, Inc.), “Preparation of1,3-diaryl-1,3-propanediones as HIV integrase inhibitors,” WO 0100578;Egbertson, M., et al., (Merck & Co. Ltd.), “HIV integrase inhibitors,”WO 9962520. Some of the patents cited above are closely related.However, none of the patents or publications describe the class ofcompounds according to the present invention. Other patents ofperipheral relationship to this invention are: Anthony, et al., (Merck &Co. Inc.), “Aza and polyaza-napthalenyl-carboxamides useful as HIVintegrase inhibitors,” WO 02/30426; Sato, et al., (Japan Tobacco Inc.),“Preparation of 4-oxoquinoline derivatives as HIV integrase inhibitors,”WO 2004046115; Sato, et al., (Japan Tobacco Inc.), “Novel 4-oxoquinolinecompounds and use thereof as HIV integrase inhibitors,” WO 2005113509;Crescenzi, et al., (Instituto Di Richerche Di Biologia Molecolare P.Angeletti SPA) “Preparation of N-substituted hydroxypyrimidinonecarboxamide inhibitors of HIV integrase,” WO 2003035077; Belyk, et al.,(Merck & Co. Inc., Instituto Di Richerche Di Biologia Molecolare P.Angeletti SPA), “Preparation ofN-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(1-methyl-1-{[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl]amino}ethyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamidepotassium salts as HIV integrase inhibitors,” WO 2006060712; Sato, etal., (Japan Tobacco Inc.), “Preparation of quinolizinone compounds asHIV integrase inhibitors,” WO 2006033422; Yoshida, et al., (Shionogi &Co. Ltd.), “Preparation of carbamoyl-pyridinone derivative having HIVintegrase inhibitory activity,” WO 2006030807; Dress, et al., (Pfizer,Inc.), “Preparation of N-hydroxy pyrrolopyridinecarboxamides asinhibitors of HIV integrase,” WO 2006027694; Naidu, et al.,(Bristol-Myers Squibb Co.), “HIV integrase inhibitors,” US 2005/0261322;Naidu, et al., (Bristol-Myers Squibb Co.), “Bicyclic heterocycles as HIVintegrase inhibitors,” US 2005/0267105; Naidu, et al., (Bristol-MyersSquibb Co.), “Bicyclic heterocycles as HIV integrase inhibitors,” US2006/0199956. While some of the patents cited above are more relatedthan others, none of the patents or publications describe the class ofcompounds according to the present invention.

The class of compounds described by us in this invention are inhibitorsof HIV-1 integrase and also possess in vitro anti-HIV activity. Anexample of the anti-HIV data in PBMC for the clinical isolate,HIV_(NL4-3), in PBMC for one of our compounds,4-(1,5-dibenzyl-1,2-dihydro-2-oxopyridin-3-yl)-2-hydroxy-4-oxobut-2-enoicacid, (8) and AZT in the same study is given below.

Compound 8 EC₉₅ 0.61 μM, CC₉₅>200 μM, Therapeutic Index (TI)>330

AZT EC₉₅ 9.42 nM, CC₉₅>1 μM, Therapeutic Index (TI)>106

At pH 7.4, the half life (t_(1/2)) of compound 8 is >41 hours. Thet_(1/2) in pooled human liver microsome for compound 8 is >6 hours.

SUMMARY OF THE INVENTION

A new class of diketo acids constructed on pyridinone scaffolds, anddesigned as inhibitors of HIV replication through inhibition of HIVintegrase, is described. These compounds can be represented by thegeneral formula I (and includes tautomers, regioisomers and geometricisomers, as well as pharmaceutically acceptable salts thereof, whereapplicable), in which the moiety illustrated as a square is a molecularscaffold made up of a pyridinone derivative. These compounds haveapplication in the prevention or treatment of infection by HIV and thetreatment of AIDS and ARC, either as the compounds, or as theirpharmaceutically acceptable salts, with pharmaceutically acceptablecarriers, used alone or in combination with antivirals,immunomodulators, antibiotics, vaccines, and other therapeutic agents,especially other anti-HIV compounds (including other anti-HIV integraseagents), which can be used to create combination anti-HIV cocktails.Methods of treating AIDS and ARC and methods of treating or preventinginfection by HIV are also described.

The present invention further relates in preferred aspects to the use ofat least one of the above compounds in combination with at least oneadditional anti-HIV agent as otherwise described herein.

DETAILED DESCRIPTION OF THE INVENTION

The following terms shall be used throughout the specification todescribe the present invention. Unless otherwise indicated, a term usedto describe the present invention shall be given its ordinary meaning asunderstood by those skilled in the art.

The term “compound”, as used herein, unless otherwise indicated, refersto any specific chemical compound disclosed herein and includestautomers, regioisomers, geometric isomers, and where applicable,optical isomers thereof, as well as pharmaceutically acceptable saltsand hydrates thereof. Within its use in context, the term compoundgenerally refers to a single compound, but also may include othercompounds such as stereoisomers, regioisomers and/or optical isomers(including racemic mixtures) as well as specific enantiomers orenantiomerically enriched mixtures of disclosed compounds. The breadthof the term “compound” shall be construed within the context of the useof the term.

The term “patient” or “subject” is used throughout the specification todescribe an animal, generally a mammal and preferably a human, to whomtreatment, including prophylactic treatment, with the compositionsaccording to the present invention is provided. For treatment of thoseinfections, conditions or disease states which are specific for aspecific animal such as a human patient, the term patient refers to thatspecific animal.

The term “effective” is used herein, unless otherwise indicated, todescribe an amount of a compound or composition or component which, incontext, is used to produce or effect an intended result, whether thatresult relates to the treatment of a viral, microbial or other diseasestate, disorder or condition associated with HIV, ARC or AIDS oralternatively, is used to produce another compound, agent orcomposition. This term subsumes all other effective amount or effectiveconcentration terms which are otherwise described in the presentapplication.

The term “scaffold” is used throughout the specification to mean apyridinone chemical structure containing at least four substituents atfive substitutable positions on this scaffold, one of which is aketoacid as otherwise defined herein and the other four of which R¹, R²,R³ and R⁴ are as defined herein.

The term “heteroaryl” shall mean a 5 or 6-membered heteroaromatic ringcontaining 1 to 2 heteroatoms selected from oxygen, nitrogen and sulfur,which heteroaromatic ring is optionally substituted with from 1 to 3substituents such as halogen, hydroxyl, C₁₋₃ alkyl, C₁₋₃ alkoxy and CF₃.The terms heteroaryl and “heteroaromatic ring” are used interchangeablyherein.

The term “human immunodeficiency virus” or “HIV” shall be used todescribe human immunodeficiency viruses 1 and 2 (HIV-1 and HIV-2).

The terms “ARC” and “AIDS” refer to syndromes of the immune systemcaused by the human immunodeficiency virus, which are characterized bysusceptibility to certain diseases and T cell counts which are depressedcompared to normal counts. HIV progresses from Category 1 (AsymptomaticHIV Disease) to Category 2 (ARC), to Category 3 (AIDS), with theseverity of the disease.

A Category 1 HIV infection is characterized by the patient or subjectbeing HIV positive, asymptomatic (no symptoms) and having never hadfewer than 500 CD4 cells. If the patient has had any of theAIDS-defining diseases listed for categories 2 (ARC) or 3 (AIDS), thenthe patient is not in this category. If the patient's t-cell count hasever dropped below 500, that patient is considered either Category 2(ARC) or Category 3 (AIDS).

A Category 2 (ARC) infection is characterized by the following criteria:The patient's T-cells have dropped below 500 but never below 200, andthat patient has never had any Category 3 diseases (as set forth below)but have had at least one of the following defining illnesses—

-   -   Bacillary angiomatosis    -   Candidiasis, oropharylgeal (thrush)    -   Candidiasis, vulvovaginal; persistent, frequent, or poorly        responsive to therapy    -   Cervical dysplasia (moderate or severe)/cervical carcinoma in        situ    -   Constitutional symptoms, such as fever (38.5 C) or diarrhea        lasting longer than 1 month    -   Hairy leukoplakia, oral    -   Herpes zoster (shingles), involving at least two distinct        episodes or more than one dermatome    -   Idiopathic thrombocytopenic purpura    -   Listeriosis    -   Pelvic inflammatory disease, particularly if complicated by        tubo-ovarian abscess    -   Peripheral neuropathy

According to the U.S. government, in Category 2 ARC, the immune systemshows some signs of damage but it isn't life-threatening.

A Category 3 (AIDS) infection is characterized by the followingcriteria:

-   -   your T-cells have dropped below 200 or    -   you have had at least one of the following defining illnesses—        -   Candidiasis of bronchi, trachea, or lungs        -   Candidiasis, esophageal        -   Cervical cancer, invasive**        -   Coccidioidomycosis, disseminated or extrapulmonary        -   Cryptococcosis, extrapulmonary        -   Cryptosporidiosis, chronic intestinal (greater than 1            month's duration)        -   Cytomegalovirus disease (other than liver, spleen, or nodes)        -   Cytomegalovirus retinitis (with loss of vision)        -   Encephalopathy, HIV-related        -   Herpes simplex: chronic ulcer(s) (greater than 1 month's            duration); or bronchitis, pneumonitis, or esophagitis        -   Histoplasmosis, disseminated or extrapulmonary        -   Isosporiasis, chronic intestinal (greater than 1 month's            duration)        -   Kaposi's sarcoma        -   Lymphoma, Burkitt's (or equivalent term)        -   Lymphoma, immunoblastic (or equivalent term)        -   Lymphoma, primary, of brain        -   Mycobacterium avium complex or M. kansasii, disseminated or            extrapulmonary        -   Mycobacterium tuberculosis, any site (pulmonary** or            extrapulmonary)        -   Mycobacterium, other species or unidentified species,            disseminated or extrapulmonary    -   Pneumocystis carinii pneumonia    -   Pneumonia, recurrent**    -   Progressive multifocal leukoencephalopathy    -   Salmonella septicemia, recurrent    -   Toxoplasmosis of brain    -   Wasting syndrome due to HIV

The term “coadministration” shall mean that at least two compounds orcompositions are administered to the patient at the same time, such thateffective amounts or concentrations of each of the two or more compoundsmay be found in the patient at a given point in time. Although compoundsaccording to the present invention may be co-administered to a patientat the same time, the term embraces both administration of two or moreagents at the same time or at different times, provided that effectiveconcentrations of all coadministered compounds or compositions are foundin the subject at a given time (but not necessarily at all times).

The term “independently” is used herein to indicate that the variable,which is independently applied, varies independently from application toapplication.

The present invention is directed to compounds of the general molecularformula I, combinations thereof, or pharmaceutically acceptable saltsthereof, in the inhibition of HIV integrase, the prevention or treatmentof HIV infections and in the treatment of AIDS and ARC. Compounds offormula I are defined as follows:

including tautomers, regioisomers, geometric isomers, and whereapplicable, optical isomers thereof, and pharmaceutically acceptablesalts thereof, wherein the pyridinone scaffold and R groups are definedas:

-   -   diketo acids with the two pyridinone scaffolds shown;

R¹ and R² are independently:

-   -   a) H,    -   b) C₁₋₆ alkyl,    -   c) C₁₋₆ fluoroalkyl,    -   d) C₁₋₆ alkyl S(O)_(n)R, wherein n selected from 0-2, R is        selected from C₁₋₃ alkyl, phenyl and substituted phenyl with        substituents selected from:        -   1) halogen,        -   2) hydroxy,        -   3) C₁₋₃ alkyl,        -   4) C₁₋₃ alkoxy,        -   5) CF₃,    -   e) C₅₋₆ cycloalkyl with 1 to 3 substituents selected from:        -   1) halogen,        -   2) hydroxy,        -   3) C₁₋₃ alkyl,        -   4) C₁₋₃ alkoxy,        -   5) CF₃,    -   f) C₁₋₆ alkenyl,    -   g) C₁₋₆ alkyl CO_(n)R^(a), wherein n selected from 1 and 2,        R^(a) selected from:        -   1) C₁₋₆ alkyl,        -   2) H,    -   h) Phenyl,    -   i) Substituted phenyl with 1 to 3 substituents selected from:        -   1) halogen,        -   2) hydroxy,        -   3) C₁₋₃ alkyl,        -   4) C₁₋₃ alkoxy,        -   5) CF₃,    -   j) Benzyl,    -   k) Substituted benzyl with 1 to 3 substituents selected from:        -   1) halogen,        -   2) hydroxy,        -   3) C₁₋₃ alkyl,        -   4) C₁₋₃ alkoxy,        -   5) CF₃,    -   l) C₂₋₆ alkyl substituted with phenyl,    -   m) C₂₋₆ alkyl substituted with phenyl, the phenyl group may be        substituted with 1 to 3 substituents selected from:        -   1) halogen,        -   2) hydroxy,        -   3) C₁₋₃ alkyl,        -   4) C₁₋₃ alkoxy,        -   5) CF₃,    -   n) R^(b)    -   o) C₁₋₆ alkyl substituted with R^(b),

Wherein each R^(b) is 5 or 6 membered heteroaromatic ring containing 1to 2 heteroatoms selected from oxygen, nitrogen and sulfur, the ringcould be substituted or not on carbon or nitrogen with 1 to 3substituents selected from:

-   -   1) halogen,    -   2) hydroxy,    -   3) C₁₋₃ alkyl,    -   4) C₁₋₃ alkoxy,    -   5) CF₃,

R³ and R⁴ are independently selected from:

-   -   a) H,    -   b) C₁₋₆ alkyl,    -   c) Halogen,    -   d) Hydroxyl,    -   e) Phenylthio,    -   f) Substituted phenylthio with 1 to 3 substituents selected        from:        -   1) halogen,        -   2) hydroxy,        -   3) C₁₋₃ alkyl,        -   4) C₁₋₃ alkoxy,        -   5) CF₃,    -   g) Benzyl,    -   h) Substituted benzyl with 1-3 substituents selected from:        -   1) halogen,        -   2) hydroxy,        -   3) C₁₋₃ alkyl,        -   4) C₁₋₃ alkoxy,        -   5) CF₃,

R⁵ is selected from:

-   -   a) CO₂R^(c), wherein R^(c) is selected from:        -   1) C₁₋₆ alkyl,        -   2) H,        -   3) sodium or other pharmaceutical acceptable salt,    -   b) P(O)(OR^(d))(OR^(e)), wherein R^(d) and R^(e) could be same        or not and that are selected from:        -   1) C₁₋₆ alkyl,        -   2) H,        -   3) sodium or other pharmaceutical acceptable salt.

Certain preferred embodiments include compounds which are based on the2-pyridinone (pyridin-2-one) scaffold in which the diketo acid moiety isat the 3-position of the pyridinone ring:

wherein R¹ and R² are independently benzyl groups or independentlysubstituted benzyl groups with 1 to 3 substituents on the phenyl ringsselected from fluorine, chlorine, C₁₋₄ alkyl, C₂₋₄ alkenyl, methoxy;wherein R³ is H, C₁₋₃ alkyl, C₂₋₃ alkenyl, fluorine, chlorine, methoxy;wherein R⁴ is H, F, Cl, OHwherein R⁵ is CO₂H or P(O)(OH)₂ or a pharmaceutically acceptable saltthereof.

Also included within the present invention are pharmaceuticalcompositions, preferably useful for inhibiting HIV integrase, comprisingof an effective amount of a compound of this invention, and apharmaceutically acceptable carrier, additive or excipient.Pharmaceutical compositions useful for treating infection by HIV or fortreating AIDS or ARC are also included by the present invention. Thepresent invention also includes methods for inhibiting the viral enzyme,HIV integrase, and a method of inhibiting HIV growth or replication, ortreating an HIV infection or for treating AIDS or ARC. In addition, thepresent invention is directed to a pharmaceutical compositioncomprising, in combination, a therapeutically effective amount of acompound of the present invention in combination with a therapeuticallyeffective amount of an agent for the treatment of AIDS selected from (i)an AIDS or HIV antiviral agent, (ii) an anti-infective agent, (iii) animmunomodulator, (iv) other useful therapeutic agents includingantibiotics and other antiviral agents.

The compounds of the present invention may have regioisomers withrespect to pyridinone scaffold and R¹, R², R³ and R⁴ and theseregioisomeric forms are included in the present invention. The compoundsmay have asymmetric centers and may occur as optical isomers and all ofthese isomeric forms are included in the present patent invention. Thecompounds may have geometric isomers and these forms are included in thepresent invention.

PLEASE PROVIDE PREFERRED EMBODIMENTS (substitutents), If APPLICABLE, forR1, R2, R3, R4, R5, Ra, Rb, Rc, Rd, Re, etc.

Tautomeric forms may also exist with compounds of the present invention.Thus, the terminology “and tautomers thereof” is used in describingtautomeric forms of compounds of formula I such as Ia and Ib (shownbelow). By naming compounds as being represented by the general formulaI and tautomers thereof, it is understood that for the purposes of thepresent invention that tautomers Ia and Ib are also included. Similarly,by referring to compound (Ia), it is understood for the purposes of thepresent application that tautomers (I) and (Ib) are also intended. Thesame holds true for references to tautomer (Ib).

When the variables involving R¹, R², R³, R⁴ and R⁵ occur more than oncein any formula I, the definition on each occurrence is independent ofits definition at every other occurrence. Combinations of pyridinonesand variables are permissible only if, in context, such combinationsresult in stable compounds.

The compounds of the present invention are useful inter alia, in theinhibition of HIV integrase, the prevention or treatment of infection byHIV and in the treatment of the disease known as AIDS. Treating AIDS orpreventing or treating infection by HIV is defined as including thetreatment of a wide range of states of HIV infection: AIDS, ARC andactual or potential exposure to HIV (e.g., through blood transfusion,exchange of body fluids, bites, needle punctures, exposure to infectedpatient blood during medical or dental procedures, and other means).

Other applications are also part of this invention. For example, thecompounds of this invention are useful in the preparation and executionof screening assays for antiviral compounds including in the isolationof viral enzyme mutants and in further understanding of the enzyme, HIVintegrase.

The present invention also provides for the use of a compound ofstructural formula (I) to make a pharmaceutical composition useful forinhibiting HIV integrase and in the treatment of AIDS or ARC.

The compounds of the present invention may be administered in the formof “well-known pharmaceutically acceptable” salts. The latter isintended to include all acceptable salts such as acetate, lactobionate,benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate,bisulfate, mandelate, bitartrate, mesylate, borate, methylbromide,bromide, methylnitrate, calcium edetate, camsylate, mucate, carbonate,napsylate, chloride, nitrate, clavulanate, N-methylglucamine, citrate,ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate,pamoate, estolate, palmitate, esylate, fumarate, phosphate, diphosphate,gluceptate, polygalacturonate, gluconate, salicylate, glutamate,stearate, glycollylarsanilate, sulfate, hexylresorcinate, subacetate,hydrabamine, succinate, hydrobromide, tannate, hydrochloride, tartrate,hydroxynaphthoate, teoclate, iodide, tosylate, isothionate,triethiodide, lactate, panoate, valerate, and others which can be usedas a dosage form for modifying the solubility or hydrolysischaracteristics or can be used in sustained release or pro-drugformulations. The pharmaceutically acceptable salts of this inventioninclude those with counterions such as sodium, potassium, calcium,lithium, magnesium, zinc, and from bases such as ammonia,ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine,choline, N,N′-dibenzylethylenediamine, chloroprocaine, diethanolamine,procaine, N-benzylphenethylamine, diethylamine, piperazine,tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide.

Also, in the case of a carboxylic acid (—COOH) or an alcohol group beingpresent, pharmaceutically acceptable esters can be employed, e.g.,acetate, maleate, pivaloyloxymethyl and others, more preferably C₁-C₂₀esters and those esters known in the art for improving solubility orhydrolysis characteristics for use as sustained release or pro-drugformulations. Pharmaceutically acceptable esters can also be employed inthe case where a phosphonic acid group [—PO(OH)₂] is present. Diketophosphonic acids attached to pyridinone scaffolds are also part of thisinvention.

Therapeutically effective amounts of the compounds of the presentinvention may be administered to patients orally, parenterally, byinhalation spray, or rectally, in dosage unit formulations containingpharmaceutically-acceptable carriers, adjuvants and vehicles includingnanoparticle drug delivery approaches. The term “pharmaceuticallyacceptable” is meant to infer that the carrier, diluent, excipient orother additive must be compatible with the other ingredients of theformulation and not deleterious to the patient or recipient.Pharmaceutical compositions may be in the form of orally-administrablesuspensions or tablets, nasal sprays and injectable preparations(injectable aqueous or oleagenous suspensions or suppositories). Thismethod of treatment is part of the invention. The administrationapproaches used (orally as Solution or suspension, immediate releasetablets, nasal aerosol or inhalation, injectable solutions orsuspensions or rectally administered in the form of suppositories)involve techniques that are well-known in the art of pharmaceuticalformulation.

The compounds of this invention can be administered orally to humans ina preferred form (such as tablets) and in a preferred dosage range ofabout 0.1 to 200 mg/kg body weight in divided doses. The specific doselevel and frequency of dosage for any particular patient may be variedand will depend upon a variety of factors including compound activity,compound metabolism and duration of action, patient age, body weight,general health, sex, diet, mode and time of administration, rate ofexcretion, drug combination, the severity of the particular condition,and the condition of the patient undergoing therapy.

The present invention also includes therapeutically effectivecombinations of the HIV integrase inhibitor compounds of formula I withone or more other therapeutic agents such as AIDS antivirals, otherantiviral agents, immunomodulators, antiinfectives, antibiotics,vaccines or other therapeutic agents. Some examples are given below.

Antiviral Agents, Anti-Infectives, Immunomodulators, OpportunisticInfection Drugs, Other Relevant Drugs in AIDS

Drug Name Manufacturer Therapeutic Use 097 Hoechst/Bayer HIV infection,AIDS, ARC (NNRT inhibitor) Amprenivir Glaxo Wellcome HIV infection,AIDS, 141W94, GW141 ARC (protease inhibitor) Abacavir (1592U89) GlaxoWellcome HIV infection, AIDS, GW 1592 ARC (RT inhibitor) AcemannanCarrington Labs (Irving, ARC TX) Acyclovir Burroughs Wellcome HIVinfection, AIDS, ARC, in combination with AZT AD-439 Tanox BiosystemsHIV infection, AIDS, ARC AD-519 Tanox Biosystems HIV infection, AIDS,ARC Adefovir dipivoxil Gilead Sciences, HIV infection AL-721 Ethigen(Los Angeles, ARC, PGL HIV positive, CA) AIDS Alpha Interferon GlaxoWellcome Kaposi's sarcoma, HIV in combination w/Retrovir Ansamycin AdriaLaboratories ARC LM 427 (Dublin, OH) Erbamont (Stamford, CT) Antibodywhich Advanced Biotherapy AIDS, ARC neutralizes pH labile Concepts(Rockville, alpha aberrant MD) Interferon AR 177 Aronex Pharm HIVinfection, AIDS, ARC Beta-fluoro-ddA National Cancer InstituteAIDS-associated diseases BMS-232623 Bristol-Myers HIV infection, AIDS,(CGP-73547) Squibb/Novartis ARC (protease inhibitor) BMS-234475Bristol-Myers HIV infection, AIDS, (CGP-61755) Squibb/Novartis ARC(protease inhibitor) CI-1012 Warner-Lambert HIV-1 infection CidofovirGilead Science CMV retinitis, herpes, papillomavirus Curdlan sulfate AJIPharma USA HIV infection Cytomegalovirus MedImmune CMV retinitis Immuneglobin Cytovene Syntex Sight threatening CMV Ganciclovir CMV RetinitisddI Bristol-Myers Squibb HIV infection, AIDS, Dideoxyinosine ARC;combination with AZT/d4T DMP-450 AVID (Camden, NJ) HIV infection, AIDS,ARC (protease inhibitor) Efavirenz (DMP-266) DuPont Merck HIV infection,AIDS, ARC (non-nucleoside RT inhibitor EL10 Elan Corp, PLC HIV infection(Gainesville, GA) Famciclovir Smith Kline Herpes zoster, herpes simplexFTC Emory University HIV infection, AIDS, ARC (RT inhibitor) GS 840Gilead HIV infection, AIDS, ARC (RT inhibitor) HBY097 Hoechst MarionRoussel HIV infection, AIDS, ARC (non-nucleoside RT inhibitor) HypericinVIMRx Pharm. HIV infection, AIDS, ARC Recombinant Human TritonBiosciences AIDS, Kaposi's sarcoma, Interferon Beta (Almeda, CA) ARCInterferon alfa-n3 Interferon Scienes ARC, AIDS Indinavir Merck HIVinfection, AIDS, ARC, asymptomatic HIV positive; combination withAZT/ddI/ddC ISIS-2922 ISIS Pharmaceuticals CMV retinitis KNI-272 Natl.Cancer Institute HIV-associated diseases Lamivudine, 3TC Glaxo WellcomeHIV infection, AIDS, ARC (RT inhibitor); also with AZT LobucavirBristol-Myers Squibb CMV infection Nelfinavir Agouron PharmaceuticalsHIV infection, AIDS, ARC (protease inhibitor) Nevirapine BoeheringerIngleheim HIV infection, AIDS, ARC (RT inhibitor) Novapren NovaferonLabs, Inc. HIV inhibitor (Akron, OH) Peptide T Peninsula Labs (Belmont,AIDS Octapeptide Sequence CA) Trisodium Astra Pharm. Products, CVVretinitis, HIV Phosphonoformate Inc. infection, other CMV PNU-140690Pharmacia Upjohn HIV infection, AIDS, ARC (protease inhibitor) ProbucolVyrex HIV infection, AIDS RBC-CD4 Sheffield Med. Tech HIV infection,AIDS, (Houston, TX) ARC Ritonavir Abbott HIV infection, AIDS, ARC(protease inhibitor) Saquinavir Hoffmann-LaRoche HIV infection, AIDS,ARC (protease inhibitor) Stavudine; d4T Bristol-Myers Squibb HIVinfection, AIDS, Didehydrodeoxythymidine ARC Valaciclovir Glaxo WellcomeGenital HSV & CMV infections Virazole Ribavirin Viratek/ICN (CostaAsymptomatic HIV Mesa, CA) positive, LAS, ARC VX-478 Vertex HIVinfection, AIDS, ARC Zalcitabine Hoffmann-LaRoche HIV infection, AIDS,ARC with AZT Zidovudine; AZT Glaxo Wellcome HIV infection, AIDS, ARC,Kaposi's sarcoma, in combination with other therapies Tenofovirdiisoproxil Gilead HIV infection, AIDS, fumarate salt (Viread ®) (RTinhibitor) Combivir ® GSK HIV infection, AIDS, (RT inhibitor) Abacavirsuccinate (or GSK HIV infection, AIDS, Ziagen ®) (reverse transcriptaseinhibitor) Fuzeon ® (or T-20) Roche/Trimeris HIV infection, AIDS, viralFusion inhibitor AS-101 Wyeth-Ayerst AIDS Bropirimine Pharmacia UpjohnAdvanced AIDS Acemannan Carrington Labs, Inc. AIDS, ARC (Irving, TX)CL246, 738 American Cyanamid AIDS, Kaposi's sarcoma Lederle Labs EL10Elan Corp, PLC HIV infection (Gainesville, GA) FP-21399 Fuki ImmunoPHARM Blocks HIV fusion with CD4+ cells Gamma Interferon Genentech ARC,in combination w/TNF Granulocyte Genetics Institute AIDS MacrophageColony Sandoz Stimulating Factor Granulocyte Hoeschst-Roussel AIDSMacrophage Colony Immunex Stimulating Factor Granulocyte Schering-PloughAIDS, combination Macrophage Colony w/AZT Stimulating Factor HIV CoreParticle Rorer Seropositive HIV Immunostimulant IL-2 Cetus AIDS, incombination Interleukin-2 w/AZT IL-2 Hoffman-LaRoche AIDS, ARC, HIV, inInterleukin-2 Immunex combination w/AZT IL-2 Chiron AIDS, increase inCD4 Interleukin-2 cell counts (aldeslukin) Immune Globulin CutterBiological Pediatric AIDS, in Intravenous (Berkeley, CA) combinationw/AZT (human) IMREG-1 Imreg (New Orleans, LA) AIDS, Kaposi's sarcoma,ARC, PGL IMREG-2 Imreg (New Orleans, LA AIDS, Kaposi's sarcoma, ARC, PGLImuthiol Diethyl Merieux Institute AIDS, ARC Dithio Carbamate Alpha-2Interferon Schering Plough Kaposi's sarcoma w/AZT, AIDSMethionine-Enkephalin TNI Pharmaceutical AIDS, ARC (Chicago, IL) MTP-PECiba-Geigy Corp. Kaposi's sarcoma Muramyl-Tripeptide Granulocyte AmgenAIDS, in combination Colony Stimulating Factor w/AZT Remune ImmuneResponse Corp. Immunotherapeutic rCD4 Genentech AIDS, ARC RecombinantSoluble Human CD4-IgG rCD4-IgG Hybrids AIDS, ARC Recombinant SolubleBiogen AIDS, ARC Human CD4 Interferon Alfa 2a Hoffman-LaRoche Kaposi'ssarcoma, AIDS, AR, combination w/AZT SK&F1-6528 Smith Kline HIVinfection Soluble T4 Thymopentin Immunobiology Research HIV infectionInstitute (Annandale, NJ) Tumor Necrosis Factor Genentech ARC, incombination (TNF) w/gamma Interferon AK602 Kumamoto University HIVinfection (entry and Japan fusion inhibitor) Alovudine Medivir, UK Ltd.HIV infection (nucleoside RT inhibitor) Amdoxovir RFS Pharma, LLCTreatment of HIV and HBV infections (nucleoside RT Inhibitor) AMD070AnorMED, Inc. HIV infection (entry and fusion inhibitor) Atazanavir(Reyataz) Bristol - Myers Squibb HIV infection (protease inhibitor)AVX754 (apricitabine) Avexa Ltd. HIV infection (nucleoside RT inhibitorBevirimat Panacos Pharmaceuticals HIV infection (maturation inhibitor)BI-201 BioInvent HIV infection (gene therapy, blocks HIV tat gene).BMS-378806 Bristol - Myers Squibb HIV infection (entry inhibitor)BMS-488043 Bristol - Myers Squibb HIV infection (entry and fusioninhibitor) BMS-707035 Bristol - Myers Squibb HIV infection (integaseinhibitor) C31G Cellegy Pharmaceuticals, HIV infection and other Incsexually transmitted diseases (STDs) Carbopol 974P ReProtect, LLC Sexualtransmission of HIV Calanolide A Sarawak MediChem HIV infection (non-Pharmaceuticals, Inc. nucleoside RT inhibitor) Carrageenan FMCBiopolymer HIV microbicide Cellulose sulfate Polydex Pharmaceuticals,Prevention of HIV infection Ltd. and other sexually transmitted diseasesCyanovirin-N Cellegy Pharmaceuticals, Prevention of sexual Inc.transmission of HIV infection Darunavir Tibotec HIV infection (co-administered with ritonavir) Delavirdine Pfizer HIV infection (non-nucleoside RT inhibitor) Dextran sulfate Ueno Fine Chemicals Preventionof transmission Industry, Ltd. of HIV Didanosine (Videx, Bristol - MyersSquibb HIV infection (nucleoside Videx EC) RT inhibitor) EfavirenzBristol - Myers Squibb HIV infection (non- nucleoside RT inhibitor)Elvucitabine Achillion Pharmaceuticals HIV infection (nucleoside RTinhibitor) Emtricitabine Gilead Sciences HIV infection (nucleoside RTinhibitor) Fosamprenavir (Lexiva) GlaxoSmithKline HIV infection(protease inhibitor) Fozivudine tidoxil Heidelberg Pharma HIV infection(entry and fusion inhibitor) GS 9137 Gilead Sciences HIV infection(integase inhibitor) GSK-873,140 (aplaviroc) GlaxoSmithKline HIVinfection (entry and fusion inhibitor) GSK-364735 GlaxoSmithKline HIVinfection (integase inhibitor) GW640385 (brecanavir) GlaxoSmithKline HIVinfection (protease inhibitor) HG0004 Human Genome Sciences HIVinfection (entry and fusion inhibitor) HGTV43 Enzo Therapeutics HIVinfection (antisense drug) Hydroxyethyl cellulose Union Carbide Preventsexual transmission of HIV INCB9471 Incyte Corporation HIV infection(entry and fusion inhibitor) KP-1461 Koronis Pharmaceuticals HIVinfection (nucleoside RT inhibitor) Lopinavir Abbott Laboratories HIVinfection (protease inhibitor) Mifepristone (VGX410, Viral Genomix HIVinfection (gene RU486) therapy, interferes with vpr) MK-0518 Merck HIVinfection (integase inhibitor) PA-457 (bevirimat) PanacosPharmaceuticals, Treatment of HIV Inc. (maturation inhibitor)Poly(I)-Poly(C12U) Hemispherx Biopharma, Biological response (Ampligen)Inc. modifier PPL-100 Merck HIV infection (protease inhibitor) PRO 140Progenics Pharmaceuticals, HIV infection (entry and Inc. fusioninhibitor) PRO 542 Progenics Pharmaceuticals, HIV infection (entry andInc. fusion inhibitor) PRO 2000 Indevus Pharmaceuticals, MicrobicideInc. Racivir Pharmasset, Inc. HIV infection (nucleoside RT inhibitor)SCH-D (vicriviroc) Schering - Plough Corp HIV infection (entry andfusion inhibitor) SP01A Samaritan Pharmaceuticals HIV infection (entryand fusion inhibitor) SPL7013 Starpharma Microbicide TAK-652 Takeda HIVinfection (entry and fusion inhibitor) Tipranavir (Aptivus) BoehringerIngelheim HIV infection (protease Pharmaceuticals inhibitor) TNX-355Tanox, Inc. HIV infection (entry and fusion inhibitor) TMC125(etravirine) Tibotec HIV infection (non- nucleoside RT inhibitor) UC-781Cellegy Pharmaceuticals, Microbicide Inc UK-427,857 (Maraviroc) PfizerHIV infection (entry and fusion inhibitor) Valproic acid Abbott Treatingseizures in HIV infection VRX496 VIRxSYS Gene therapy Zalcitabine(Hivid) Roche HIV infection (nucleoside RT inhibitor) Valganciclovir(Valcyte) Roche Antiviral (CMV retinitis in AIDS) Clindamycin withPharmacia Upjohn PCP Primaquine Fluconazole Pfizer Cryptococcalmeningitis, candidiasis Pastille Squibb Corp. prevention of oralNystatin Pastille candidiasis Ornidyl Merrell Dow PCP EflornithinePentamidine LyphoMed (Rosemont, PCP treatment Isethionate (IM & IV) IL)Trimethoprim Antibacterial Trimethoprim/sulfa Antibacterial PiritreximBurroughs Wellcome PCP treatment Pentamidine isethionate FisonsCorporation PCP prophylaxis Spiramycin Rhone-Poulenc Cryptosporidialdiarrhea Intraconazole-R51211 Janssen Pharm Histoplasmosis; cryptococcalmeningitis Trimetrexate Warner-Lambert PCP Daunorubicin NeXstar, SequusKarposi's sarcoma Recombinant Human Ortho Pharm. Corp. Severe anemiaassocated Erythropoietin w/AZT therapy Recombinant Human SeronoAIDS-related wasting, Growth Hormone cachexia Megestrol AcetateBristol-Myers Squibb Treatment of anorexia associated w/AIDSTestosterone Alza, Smith Kline AIDS-related wasting Total EnteralNutrition Norwich Eaton Diarrhea and Pharmaceuticals malabsorption inAIDS Aldesleukin (Proleukin) Chiron Corp Biological response modifierAmphotericin B (Abelecet, Pfizer, Bristol - Myers Antifungal AmBisome,Amphocin, Squibb Amphotec, Fungizone) Azithromycin (Zithromax) PfizerAntibacterial antibiotic Calcium hydroxyapatite Bioform Medical, Inc.Dermal filler (Radiesse Doxorubicin (liposomal) Ortho Biotech, AlzaAntineoplastic (Doxil) Corporation Dronabinol (Marinol) UnimedPharmaceuticals, Antiemetics Inc. Entecavir (Baraclude) Bristol-MyersSquibb Antiviral Epoetin alfa (Epogen, Ortho Biotech Anemia Procrit)Etoposide (Etopophos Pfizer, Bristol-Myers Antineoplastic (phosphatesalt), Toposar, Squibb VePesid) Fluconazole (Diflucan) Pfizer AntifungalInterferon alfa-2 (Intron A Roche, Schering - 3 Plough Biologicalresponse (2b), Roferon-A (2a) modifiers Isoniazid (Nydrazid) Sandoz,Hoffmann La- Antimycobacterial Roche Itraconazole (Sporanox) OrthoBiotech, Janssen Antifungal Pharmaceutica Megestrol (Megace, Bristol -Myers Squibb Anticachectic Megace ES) Paclitaxel (Onxol, Taxol)Bristol - Myers Squibb, Antineoplastic IVAX PharmaceuticalsPeginterferon alfa-2 (PEG- Roche, Schering - Plough Antiviral Intron(2b), Pegasys (2a)) Pentamidine (Nebupent) American PharmaceuticalAntiprotozoal Partners, Fujisawa Health Care, Inc. Poly-L-lactic acidDermik Laboratories Dermal Filler (Sculptra) Rifabutin (Mycobutin)Pharmacia Corporation Antimycobacterial Rifampin (Rifadin; AventisPharmaceuticals Antimycobacterial Rimactane) Somatropin PharmaciaCorporation, Synthetic human growth Serono Inc hormone Sulfamethoxazole/Alpha care Inc, Women Antibacterial Trimethoprim (Bactrim, First HealthCare, King Septra) (Serostim) Pharmaceuticals Testosterone (Androderm,Pfizer Inc, Unimed Androgens Androgel, Depo- Pharmaceuticals, Inc., AlzaTestosterone) Corporation, Watson Laboratories Trimetrexate (Neutrexin)United States Bioscience Antiprotozoal Inc, Medimmune, Inc.

Chemical Synthesis

REPRESENTATIVE EXAMPLE 14-(1,5-dibenzyl-1,2-dihydro-2-oxopyridin-3-yl)-2-hydroxy-4-oxobut-2-enoicacid (8) The relevant scheme (1) is shown below.

A mixture of pyridine-2-amine 1 (14.1 g, 149.8 mmol) and benzylchloride(36.0 g, 284.6 mmol) was heated to 180° C. until the mixture began toboil [Kowalski, J. Heterocycl. Chem. 28, 875-879 (1991)]. Thetemperature was then gradually raised during 3 h to 250° C. andmaintained for 24 h. After cooling, the reaction mixture was washed outfrom the flask with MeOH (60 mL) and treated with 10% aqueous NH₄OH (40mL). After addition of water (200 mL), the resulting oil was extractedwith CHCl₃ (2×200 mL), dried over anhydrous Na₂SO₄, and CHCl₃ distilledoff. The residue was separated by distillation under reduced pressure.The fraction collected at 130-135° C./1 mm Hg was further purified byflash chromatography on silica gel (EtOAc:hexane, 7:3). Yield 9.2 g(34%), white solid, mp 79-80° C. ¹H NMR (CDCl₃, 500 MHz): δ 3.87 (s, 2H,CH₂), 4.43 (bs, 2H, NH₂), 6.48 (d, 1H, CH J=8.5 Hz), 7.19-7.33 (m, 6H,Ar—H and CH), 7.99 (d, 1H, CH, J=1.5 Hz). ¹³C NMR (CDCl₃, 125 MHz): δ38.2, 108.7, 126.1, 126.4, 128.5, 128.7, 128.9, 128.9, 138.6, 140.9,147.7, 156.8.

Step 2: 5-Benzyl-3-bromopyridin-2-amine (3)

To a stirred solution of 5-benzylpyridin-2-amine 2 (6.0 g, 32.3 mmol) inCH₂C₁₂ (100 mL) cooled to 0° C. was added bromine (5.1 g, 32.3 mmol)dropwise [Kelly, et al., J. Am. Chem. Soc. 112, 8024-8034 (1990)]. Thebromine decolorized immediately and the mixture was left stirring for 30min. The mixture was shaken with saturated NaHCO₃ solution (100 mL), theorganic layer was then dried over anhydrous Na₂SO₄, and distilled off togive a yellow residue which was purified by flash chromatography onsilica gel (EtOAc:hexane, 3:7). Yield 7.3 g (86%), white solid, mp110-111° C. ¹H NMR (CDCl₃, 500 MHz): δ 3.86 (s, 2H, CH₂), 4.88 (bs, 2H,NH₂), 7.19-7.35 (m, 5H, Ar—H), 7.50 (d, 1H, CH, J=1.5 Hz), 7.94 (d, 1H,CH, J=1.0 Hz). ¹³C NMR (CDCl₃, 125 MHz): δ 37.7, 104.6, 126.4, 126.4,128.1, 128.6, 128.6, 128.7, 140.2, 140.8, 146.7, 154.0; HRMS (M+H)⁺calcd for C₁₂H₁₃BrN₂ 263.0184, found 263.0184.

Step 3: 5-Benzyl-3-bromopyridin-2(1H)-one (4)

To a stirred solution of 5-benzyl-3-bromopyridin-2-amine 3 (0.2 g, 0.7mmol) in DMF (4 mL) was added water (2 drops) followed by t-butylnitrite (0.378 g, 3.6 mmol) and the reaction mixture stirred at RT for30 min. DMF and the excess reagent were distilled off, and the residuepurified by flash chromatography on silica gel (EtOAc:hexane, 1:1).Yield 7.3 g (86%), white solid, mp 151-152° C. ¹H NMR (CDCl₃, 500 MHz):δ 3.77 (s, 2H, CH₂), 7.17-7.36 (m, 6H, Ar—H and CH), 7.76 (d, 1H, CH,J=1.5 Hz) 13.25 (bs, 1H, NH). ¹³C NMR (CDCl₃, 125 MHz): δ 37.3, 115.4,121.0, 126.9, 128.8, 128.8, 128.9, 128.9, 132.4, 138.5, 145.3, 161.0;HRMS (M+H)⁺ calcd for C₁₂H₁₁BrNO 264.0024, found 264.0014.

Step 4: 1,5-Dibenzyl-3-bromopyridin-2(1H)-one (5)

To a suspension of 5-benzyl-3-bromopyridin-2(1H)-one 4 (3.5 g, 13.5mmol) in dry DMF (100 mL) was added NaH 60% suspension in mineral oil(0.5 g, 16.2 mmol) and stirred for 30 min, followed by the addition ofbenzyl bromide (0.1.36 g, 7.9 mmol) and mixture further stirred for 1 hat RT. DMF was distilled off and the residue redissolved in EtOAc (250mL), washed with brine solution (2×100 mL), dried over anhydrous Na₂SO₄and EtOAc distilled off to give a yellow syrup, which was purified bycolumn chromatography on silica gel (EtOAc:Hexane, 4:6) to give 5. Yield3.8 g (83%), yellow solid, mp 89-90° C. ¹H NMR (CDCl₃, 500 MHz): δ 3.69(s, 2H, CH₂), 5.18 (s, 2H, CH₂), 7.11 (d, 1H, CH, J=2 Hz), 7.12-7.39 (m,10H, Ar—H), 7.60 (d, 1H, CH, J=2 Hz), ¹³C NMR (CDCl₃, 125 MHz): δ 37.4,53.5, 117.1, 119.1, 126.9, 128.2, 128.2, 128.3, 128.3, 128.6, 128.8,128.8, 128.9, 128.9, 134.6, 135.8, 138.7, 143.0, 158.3. HRMS (M+H)⁺calcd for C₁₉H₁₇BrNO 354.0494, found 354.0455.

Step 5: 3-Acetyl-1,5-dibenzyl-3-pyridin-2(1H)-one (6)

A mixture of 1,5-dibenzyl-3-bromopyridin-2(1H)-one 5 (1.0 g, 2.8 mmol)bis(triphenylphosphine)palladium(II) chloride (0.19 g, 0.28 mmol) andethoxyvinyl(tributyl)tin (2.03 g, 5.6 mmol) in dry DMF (50 mL) washeated under N₂ at 70° C. for 1 h. DMF was distilled off and theresulting residue redissolved in EtOAc (50 mL) and filtered through apad of celite. EtOAc fraction was stirred with 1 N HCl (30 mL) for 15min, washed with water (2×30 mL), and dried over anhydrous Na₂SO₄ anddistilled off to give a yellow residue which was purified by flashchromatography on silica gel (EtOAc:hexane, 2:8). Yield 0.86 g (97%),yellow oil. ¹H NMR (CDCl₃, 500 MHz): δ 2.73 (s, 3H, CH₃), 3.75 (s, 2H,CH₂), 5.19 (s, 2H, CH₂), 7.14-7.40 (m, 11H, Ar—H and CH), 8.04 (d, 1H,CH, J=3 Hz). ¹³C NMR (CDCl₃, 125 MHz): δ 31.1, 37.5, 52.5, 118.6, 126.8,127.8, 127.8, 127.9, 128.2, 128.2, 128.6, 128.6, 128.8, 128.8, 129.0,135.8, 138.8, 140.7, 144.8, 160.4, 198.0; HRMS (M+H)⁺ calcd forC₂₁H₂₀NO₂ 318.1494, found 318.1461.

Step 6:Methyl-4-(1,5-dibenzyl-1,2-dihydro-2-oxopyridin-3-yl)-2-hydroxy-4-oxobut-2-enoate(7)

To a stirred solution of 3-acetyl-1,5-dibenzyl-3-pyridin-2(1H)-one 6(0.1 g, 0.31 mmol) in THF (5 mL) was added Na-t-butoxide (0.30 g, 3.1mmol) and the reaction mixture stirred for 15 min. A solution ofdimethyl oxalate (0.37 g, 3.1 mmol) in THF (5 mL) was added at RT andstirred for 2 h. THF was distilled off and 1 N HCl (1 mL) was added andextracted with EtOAc (2×10 mL), washed with saturated brine solution(4×20 mL), dried over anhydrous sodium sulfate and EtOAc distilled offto give a brown residue which was purified first by ion exchangechromatography (Diethylamino sephadex anion exchange resin, (CH₃CN:H₂O,1:1) and then by flash chromatography on silica gel (CHCl₃:MeOH,9.9:0.1). Yield 0.054 g (44%), yellow oil. ¹H NMR (CDCl₃, 500 MHz): δ3.79 (s, 2H, CH₂), 3.91 (s, 3H, CH₃), 5.21 (s, 2H, CH₂), 7.15-7.42 (m,11H, Ar—H and CH), 7.98 (s, 1H, olefenic CH), 8.24 (d, 1H, CH, J=2.5Hz), ¹³C NMR (CDCl₃, 100 MHz): δ 37.5, 52.7, 53.0, 101.8, 119.0, 123.4,126.9, 128.0, 128.0, 128.3, 128.6, 128.6, 128.9, 129.0, 129.0, 129.1,135.6, 138.6, 141.4, 145.0, 159.5, 162.6, 172.2, 185.5; HRMS (M+H)⁺calcd for C₂₄H₂₂NO₅ 404.1498, found 404.1411.

Step 7:4-(1,5-Dibenzyl-1,2-dihydro-2-oxopyridin-3-yl)-2-hydroxy-4-oxobut-2-enoicacid (8)

To a stirred solution ofmethyl-4-(1,5-dibenzyl-1,2-dihydro-2-oxopyridin-3-yl)-2-hydroxy-4-oxobut-2-enoate7 (0.069 g, 0.17 mmol) in MeOH (5 mL) at 0° C. was added a solution of1N NaOH (0.5 mL) and reaction mixture allowed to stir at 0° C. for 30min. Reaction was then allowed to stir at ambient temperature for 1 h.The reaction mixture was neutralized with 1 N HCl, the solid separatedwas filtered and dried under vacuum. Recrystallization with EtOAc/Hexanegave yellow solid. Yield 0.034 g (52%), yellow solid, mp 158-159° C. ¹HNMR (CDCl₃, 500 MHz): δ 3.82 (s, 2H, CH₂), 5.26 (s, 2H, CH₂), 7.16-7.39(m, 10H, Ar—H), 7.45 (d, 1H, CH, J=2 Hz), 7.98 (s, 1H, olefenic CH),8.26 (d, 1H, CH, J=2 Hz), ¹³C NMR (CDCl₃, 125 MHz): δ 37.5, 53.3, 100.8,119.8, 123.1, 127.0, 128.2, 128.5, 128.5, 128.6, 128.6, 128.9, 128.9,129.0, 129.1, 129.1, 135.2, 138.4, 141.3, 145.1, 159.5, 162.3, 173.7;HRMS (M+H)⁺ calcd for C₂₃H₂₀NO₅ 390.1341, found 390.1342.

REPRESENTATIVE EXAMPLE 24-(1,5-dibenzyl-1,4-dihydro-4-oxopyridin-3-yl)-2-hydroxy-4-oxobut-2-enoicacid (16) The relevant scheme (2) is shown below.

Step 1: 3,5-Dibromo-pyridin-4-one (10)

To an ice-cooled solution of pyridine-4-one 9 (6.98 g, 73.4 mmol) andKOH (9.52 g, 146.8 mmol) in water (140 mL) was added bromine (7.58 mL,147.5 mmol) dropwise over 30 min [Spivey, et al., J. Org. Chem. 65,3154-3159 (2000)]. After an additional 30 min, the precipitate wasfiltered off, washed with a copious amount of water, and dried in vacuo.Yield 16.17 g (87%), yellow solid, mp 320° C. (sublimes). ¹H NMR(DMSO-d₆, 500 MHz): δ 12.3 (s, 1H), 8.26 (s, 2H). ¹³C NMR (DMSO-d₆, 125MHz): δ 167.5, 138.2, 138.2, 111.8, 111.8.

Step 2: 3-Bromo-5-(hydroxy-phenyl-methyl)-pyridin-4-one (11)

To a heterogeneous mixture of 3,5-dibromo-pyridin-4-one 10 (0.313 g,1.24 mmol) in anhydrous THF (4 mL) at −78° C. under nitrogen atmospherewas added phenylmagnesium bromide solution (1.36 mL of 1 M solution inTHF, 1.36 mmol) [Borzilleri, et al., U.S. Pat. 20050245530]. Afterstirring for 15 min, n-BuLi solution (0.68 mL of 2 M solution incyclohexane, 1.36 mmol) was added and the reaction mixture stirred for15 min at −78° C. under nitrogen atmosphere. To this mixture was addedbenzaldehyde (0.26 mL, 2.6 mmol) and the mixture was stirred for 2 h at−78° C. The reaction mixture was quenched by adding HOAc (0.38 mL) andTFA (0.38 mL), concentrated in vacuo and the residue was purified byflash column chromatography on silica gel (dichloromethane:methanol,95:5). Yield 0.125 g (36%), white solid, 123-124° C. ¹H NMR (MeOH— d₄,500 MHz): δ 8.09 (s, 1H), 7.81 (s, 1H), 7.38-7.17 (m, 5H), 5.92 (s, 1H),3.83 (s, 2H). ¹³C NMR (MeOH— d₄, 125 MHz): δ 174.3, 144.4, 139.7, 135.8,133.6, 129.4, 129.3, 128.6, 128.0, 128.0, 114.8, 70.8.

Step 3: 3-Benzyl-5-bromopyridin-4-one (12)

A mixture of 3-bromo-5-(hydroxyl-phenyl-methyl)pyridin-4-one 11 (0.125g, 91 mmol), TFA (16 mL) and Et₃SiH in anhydrous dichloromethane (30 mL)was stirred at rt for 10 h [Borzilleri, et al., U.S. Pat. 20050245530].The reaction mixture was concentrated in vacuo and the residue purifiedby flash column chromatography on silica gel (dichloromethane:methanol,98:2). Yield 0.081 g (69%), white solid. ¹H NMR (MeOH— d₄, 500 MHz): δ8.12 (s, 1H), 7.47 (s, 1H), 7.29-7.17 (m, 5H), 3.83 (s, 2H). ¹³C NMR(MeOH—d₄, 125 MHz): δ 175.2, 140.7, 139.5, 136.9, 130.8, 130.0, 130.0,129.5, 129.5, 127.3, 114.1, 34.9.

Step 4: 1,3-Dibenzyl-5-bromo-1H-pyridin-4-one (13)

A mixture of 3-benzyl-5-bromopyridin-4-one 12 (0.57 g, 2.16 mmol) andNaOEt (0.89 mL, 2.37 mmol) in absolute ethanol (20 mL) was refluxed withbenzyl chloride (0.30 mL, 2.59 mmol) for 1 h under nitrogen. The solventwas distilled off to give a yellow residue which was purified by flashcolumn chromatography on silica gel (dichloromethane:methanol, 98:2).Yield 1.31 g (96.7%), yellow solid, mp 120-121° C. ¹H NMR (CDCl₃, 500MHz): δ 7.67 (d, 1H, J=2.4), 7.32-7.07 (m, 10H), 4.83 (s, 1H), 3.78 (s,2H). ¹³C NMR (CDCl₃, 125 MHz): δ 172.2, 139.6, 139.1, 137.6, 134.7,129.9, 129.9, 129.3, 129.3, 129.2, 129.0, 128.6, 128.6, 127.5, 127.6,126.4, 114.1, 60.3, 34.4. HRMS (M+H)⁺ calcd for C₁₉H₁₆BrNO 354.0494,found 354.0499.

Step 5: 3-Acetyl-1,5-dibenzyl-1H-pyridin-4-one (14)

A mixture of 1,3-dibenzyl-5-bromo-1H-pyridin-4-one 13 (1.31 g, 2.70mmol), tributyl-(1-ethoxyvinyl)tin (1.80 mL, 5.18 mmol) anddichlorobis(triphenylphosphine)-palladium(II) (0.26 g, 0.37 mmol) inanhydrous DMF (20 mL) was stirred under nitrogen atmosphere at 95° C.for 8 h. The reaction mixture was extracted with ethyl acetate (3×50mL), washed with 1N HCl (3×50 mL), and solvent distilled off. Theresidue was purified by flash column chromatography on silica gel(dichloromethane:methanol, 98:2). Yield 1.06 g (90%), yellow oil. ¹H NMR(CDCl₃, 500 MHz): δ 8.19 (d, 1H, J=2.6), 7.39-7.10 (m, 10H), 6.90 (d,1H, J=2.5), 4.89 (s, 2H), 3.81 (s, 2H), 2.74 (s, 3H). HRMS (M+H)⁺ calcdfor C₂₁H₁₉NO₂ 318.1494, found 318.1493.

Step 6: Methyl4-(1,5-dibenzyl-4-oxo-1,4-dihydro-pyridin-3-yl)-2-hydroxy-4-oxo-but-2-enoate(15)

To a stirred solution of sodium t-butoxide (0.52 g, 5.23 mmol) inanhydrous THF (13 mL) at room temperature was added dropwise dimethyloxalate (0.42 g, 3.48 mmol) in THF (6 mL) followed by3-acetyl-1,5-dibenzyl-1H-pyridin-4-one 14 (0.55 g, 1.74 mmol) in THF (8mL). The resulting mixture was stirred at room temperature for 4 h andthen acidified (pH=6). The crude product was extracted with ethylacetate (100 mL), washed with water (2×100 mL) and brine (2×100 mL), anddried over anhydrous sodium sulfate and the solvent was distilled off.The residue was purified by ion exchange chromatography (diethylaminosephadex anion exchange resin (CH₃CN:H₂O, 1:1) and then by flashchromatography on silica gel (chloroform, 100%). Yield 0.44 g (63%), mp148-150° C. ¹H NMR (CDCl₃, 500 MHz): δ 8.34 (d, J=2.5, 1H), 8.12 (s,1H), 7.40-7.12 (m, 10H), 6.91 (d, J=2.3, 1H), 4.94 (s, 2H), 3.88 (s,3H), 3.82 (s, 2H). ¹³C NMR (CDCl₃, 125 MHz): δ 187.2, 175.2, 170.3,162.7, 143.9, 138.4, 136.9, 136.1, 133.8, 129.4, 129.5, 129.3, 129.1,129.1, 128.7, 128.6, 127.5, 127.4, 126.5, 120.2, 102.4, 61.2, 53.0,33.5. HRMS (M+H)⁺ calcd for C₂₄H₂₂NO₅ 404.1498, found 404.1497.

Step 7:4-(1,5-dibenzyl-1,4-dihydro-4-oxopyridin-3-yl)-2-hydroxy-4-oxobut-2-enoicacid (16)

A mixture ofmethyl-4-(1,5-dibenzyl-1,4-dihydro-4-oxopyridin-3-yl)-2-hydroxy-4-oxobut-2-enoate15, (0.080 g, 0.19 mmol) and 1 N NaOH (4 mL) in THF (12 mL) was stirredat 0° C. for 4 h. THF was distilled off and the residue acidified with 1N HCl and extracted with EtOAc (2×25 mL), washed with brine solution(1×25 mL), dried over anhydrous Na₂SO₄ and EtOAc distilled off to give ayellow solid. The crude solid was triturated with diethylether, filteredand dried under vacuum. Finally the solid was triturated withchloroform, filtered and dried under vacuum for 24 h. Yield 0.065 g(84%), yellow solid, mp 140-142° C. ¹H NMR (CDCl₃+MeOH-d₄, 500 MHz): δ3.80 (s, 2H, CH₂), 4.97 (s, 2H, CH₂), 6.95 (t, 1H, CH, J=1 Hz),7.13-7.40 (m, 11H, Ar—H and olefenic CH), 8.36 (d, 1H, CH, J=2.5 Hz).¹³C NMR (CDCl₃, 125 MHz): δ 33.4, 61.2, 120.5, 126.5, 127.5, 127.6,128.6, 128.7, 128.7, 129.1, 129.1, 129.2, 129.2, 129.2, 129.4, 133.8,135.9, 137.2, 138.2, 143.8, 163.8, 175.4. HRMS (M+H)⁺ calcd forC₂₃H₂₀NO₅ 390.1341, found 390.1343.

1. A compound according to the general structure of formula I:

wherein the scaffold is independently the 2- and 4-pyridinonesidentified herein and their regioisomers; R¹ and R² are eachindependently H, C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, unsubstituted orsubstituted C₅₋₆ cycloalkyl, C₁₋₆ alkenyl, unsubstituted or substitutedphenyl, unsubstituted or substituted benzyl, C₂₋₆ alkyl phenyl whichphenyl moiety may be optionally substituted, unsubstituted orsubstituted heteroaryl, C₁₋₆ alkyl substituted with a heteroaryl groupwhich heteroaryl group is optionally substituted, C₁₋₆ alkyl S(O)R oralkyl (SO₂)R where R is alkyl, phenyl or substituted phenyl, C₁₋₆ alkylCO₂R^(a) where R^(a) is C₁₋₆ alkyl or H, C₁₋₆ alkyl COR^(a) where R^(a′)is C₁₋₆ alkyl; R³ and R⁴ are independently selected from H, C₁₋₆ alkyl,halogen, hydroxyl, unsubstituted or substituted benzyl, or unsubstitutedor substituted phenylthio; R⁵ is CO₂R^(c) or P(O)(OR^(c))(OR^(c)), whereeach R^(c) is independently from H and C₁₋₆ alkyl, Or a pharmaceuticallyacceptable salt thereof.
 2. A compound of claim 1 according to thestructure:

wherein R¹ and R² are each independently a benzyl group or a substitutedbenzyl group with 1 to 3 substituents on the aromatic ring selected fromhalogen, hydroxyl, methoxy, methyl, ethyl, propyl, CF₃, or a —CH₂R^(b)group where R^(b) is a 5- or 6-membered heteroaryl group; R³ and R⁴ areindependently H, C₁₋₆ alkyl, halogen, benzyl, substituted benzyl,phenylthio, or substituted phenylthio with 1 to 3 substitutents on thephenyl ring selected from halogen, hydroxyl, methoxy, methyl, ethyl,propyl, CF₃; wherein R⁵ is CO₂R where R is selected from H and C₁₋₆alkyl, or a pharmaceutically acceptable salt thereof.
 3. The compound ofclaim 1 according to the structure:

wherein R¹ and R² are each independently a benzyl group or substitutedbenzyl group with 1 to 3 substituents on the aromatic ring selected fromhalogen, hydroxyl, methoxy, methyl, ethyl, propyl, CF₃ or wherein R¹ andR² are independently —CH₂R^(b) where R^(b) is a 5- or 6-memberedheteroaromatic ring; wherein R³ and R⁴ are independently H, C₁₋₆ alkyl,halogen, benzyl, substituted benzyl, phenylthio, or substitutedphenylthio with 1 to 3 substitutents on the phenyl ring selected fromhalogen, methoxy, methyl, ethyl, propyl, CF₃; wherein R⁵ isP(O)(OR)(OR), where the R groups could be the same or not and areselected from H or C₁₋₆ alkyl, or a pharmaceutically acceptable saltthereof.
 4. A compound of claim 1 according to the structure:

wherein R¹ and R² are each independently a benzyl group or a substitutedbenzyl group with 1 to 3 substituents on the aromatic ring selected fromhalogen, hydroxyl, methoxy, methyl, ethyl, propyl, CF₃, or a —CH₂R^(b)group where R^(b) is a 5- or 6-membered heteroaryl group; R³ and R⁴ areindependently H, C₁₋₆ alkyl, halogen, benzyl, substituted benzyl,phenylthio, or substituted phenylthio with 1 to 3 substitutents on thephenyl ring selected from halogen, hydroxyl, methoxy, methyl, ethyl,propyl, CF₃; wherein R⁵ is CO₂R where R is selected from H and C₁₋₆alkyl, or a pharmaceutically acceptable salt thereof.
 5. A compound ofclaim 1 according to the structure:

wherein R¹ and R² are each independently a benzyl group or substitutedbenzyl group with 1 to 3 substituents on the aromatic ring selected fromhalogen, hydroxyl, methoxy, methyl, ethyl, propyl, CF₃ or wherein R¹ andR² are independently —CH₂R^(b) where R^(b) is a 5- or 6-memberedheteroaromatic ring; wherein R³ and R⁴ are independently H, C₁₋₆ alkyl,halogen, benzyl, substituted benzyl, phenylthio, or substitutedphenylthio with 1 to 3 substitutents on the phenyl ring selected fromhalogen, methoxy, methyl, ethyl, propyl, CF₃; wherein R⁵ isP(O)(OR)(OR), where the R groups could be the same or not and areselected from H or C₁₋₆ alkyl, or a pharmaceutically acceptable saltthereof.
 6. A compound according to claim 1 selected from the groupconsisting of4-(1,5-dibenzyl-1,2-dihydro-2-oxopyridin-3-yl)-2-hydroxy-4-oxobut-2-enoicacid;4-(1,5-dibenzyl-1,4-dihydro-4-oxopyridin-3-yl)-2-hydroxy-4-oxobut-2-enoicacid; 3-Acetyl-1,5-dibenzyl-3-pyridin-2(1H)-one;3-Acetyl-1,5-dibenzyl-1H-pyridin-4-one;Methyl-4-(1,5-dibenzyl-1,2-dihydro-2-oxopyridin-3-yl)-2-hydroxy-4-oxobut-2-enoate;and Methyl4-(1,5-dibenzyl-4-oxo-1,4-dihydro-pyridin-3-yl)-2-hydroxy-4-oxo-but-2-enoate,or a pharmaceutically acceptable salt thereof.
 7. The compound4-(1,5-dibenzyl-1,2-dihydro-2-oxopyridin-3-yl)-2-hydroxy-4-oxobut-2-enoicacid;4-(1,5-dibenzyl-1,4-dihydro-4-oxopyridin-3-yl)-2-hydroxy-4-oxobut-2-enoicacid, or a pharmaceutically acceptable salt thereof.
 8. A compound ofclaim 1 according to the structure:

wherein R¹ and R² are independently benzyl groups or substituted benzylgroups with 1 to 3 substituents on the phenyl rings selected from thegroup consisting of fluorine, chlorine, C₁₋₄ alkyl, C₂₋₄ alkenyl andmethoxy; R³ is H, C₁₋₃ alkyl, C₂₋₃ alkenyl, fluorine, chlorine ormethoxy; R⁴ is H, F, Cl or OH; and R⁵ is CO₂H or P(O)(OH)₂, or apharmaceutically acceptable salt thereof.
 9. The compound according toclaim 1 wherein at least one of R¹ and R² is a benzyl group.
 10. Thecompound according to claim 1 wherein both R¹ and R² are benzyl groups11. The compound according to claim 8 wherein both R¹ and R² are benzylgroups.
 12. The compound according to claim 1 wherein R³ and R⁴ areindependently H, methyl, fluorine or chlorine.
 13. The compoundaccording to claim 9 wherein R³ and R⁴ are independently H, methyl,fluorine or chlorine.
 14. The compound according to claim 10 wherein R³and R⁴ are independently H, methyl, fluorine or chlorine.
 15. Thecompound according to claim 11 wherein R³ and R⁴ are independently H,methyl, fluorine or chlorine.
 16. The compound according to claim 1wherein R³ and R⁴ are independently H, fluorine or chlorine.
 17. Thecompound according to claim 8 wherein R³ and R⁴ are independently H,fluorine or chlorine.
 18. The compound according to claim 1 wherein R³and R⁴ are each H.
 19. The compound according to claim 8 wherein R³ andR⁴ are each H
 20. The compound according to claim 12 wherein R³ and R⁴are each H.
 21. The compound according to claim 1 wherein R⁵ is CO₂H ora pharmaceutically acceptable salt thereof.
 22. The compound accordingto claim 8 wherein R⁵ is CO₂H or a pharmaceutically acceptable saltthereof.
 23. The compound according to claim 9 wherein R⁵ is CO₂H or apharmaceutically acceptable salt thereof.
 24. The compound according toclaim 10 wherein R⁵ is CO₂H or a pharmaceutically acceptable saltthereof.
 25. The compound according to claim 11 wherein R⁵ is CO₂H or apharmaceutically acceptable salt thereof.
 26. The compound according toclaim 12 wherein R⁵ is CO₂H or a pharmaceutically acceptable saltthereof.
 27. The compound according to claim 13 wherein R⁵ is CO₂H or apharmaceutically acceptable salt thereof.
 28. The compound according toclaim 14 wherein R⁵ is CO₂H or a pharmaceutically acceptable saltthereof.
 29. A pharmaceutical composition comprising a therapeuticallyeffective amount of a compound according to claim 1 and apharmaceutically acceptable carrier, additive or excipient.
 30. Thepharmaceutical composition of claim 29 wherein said composition inhibitsHIV integrase, both wild type and mutants, in a human host.
 31. Apharmaceutical composition comprising a therapeutically effective amountof a compound according to claim 1 in combination with a therapeuticallyeffective amount of at least one compound selected from the groupconsisting of i) an additional anti-HIV agent, ii) an anti-infectiveagent other than an anti-HIV agent, iii) an immunomodulator, iv) othercombination agent selected from the table shown on pages 16-27, herein,and a pharmaceutically acceptable carrier, additive or excipient. 32.The composition according to claim 31 wherein said anti-infective agentis an antiviral agent selected from the group consisting of a proteaseinhibitor, a reverse transcriptase inhibitor, an additional integraseinhibitor or a combination thereof.
 33. The composition of claim 32wherein said reverse transcriptase inhibitor is a nucleoside compound.34. The composition of claim 32 wherein said reverse transcriptaseinhibitor is a non-nucleoside compound.
 35. The composition of claim 32wherein the said additional integrase inhibitor is a compound other thana pyrimidinone compound.
 36. The composition of claim 29 in oral orparenteral dosage form.
 37. The composition of claim 30 in oral orparenteral dosage form.
 38. The composition according to claim 29formulated for administration as an inhalation spray or a rectalsuppository.
 39. The composition according to claim 30 formulated foradministration as an inhalation spray or a rectal suppository.
 40. Amethod of preparing a pharmaceutical composition comprising combining acompound of claim 1 with a pharmaceutically-acceptable carrier, additiveor excipient to produce a mixture and preparing an oral or parenteraldosage form from said mixture.
 41. A method of treating an HIV infectionin a patient, said method comprising administering to said patient aneffective amount of a composition according to claim 29 to said patient.42. A method of treating an HIV infection in a patient, said methodcomprising administering to said patient an effective amount of acomposition according to claim 30 to said patient.
 43. A method ofreducing the likelihood of an HIV infection in a patient at risk forsaid infection, said method comprising administering to said patient aneffective amount of a composition according to claim 29 to said patient.44. A method of reducing the likelihood of an HIV infection in a patientat risk for said infection, said method comprising administering to saidpatient an effective amount of a composition according to claim 30 tosaid patient.
 45. A method of treating a patient with AIDS or ARCcomprising administering to said patient a therapeutically effectiveamount of the composition according to claim
 29. 46. A method oftreating a patient with AIDS or ARC comprising administering to saidpatient a therapeutically effective amount of the composition accordingto claim
 30. 47. A method of inhibiting HIV integrase in a subject, saidmethod comprising administering to said subject a therapeuticallyeffective amount of a compound according to claim 1 to said subject. 48.The method of claim 47 wherein said subject is a human.